Original A systematic review of the drug‑induced

Article
Stevens‑Johnson syndrome and toxic epidermal
necrolysis in Indian population

Tejas K. Patel, Manish J. Barvaliya1, Dineshchandra Sharma,

Chandrabhanu Tripathi1

Department of Pharmacology, ABSTRACT

GMERS Medical College, Gotri,
Vadodara, and 1Government Background: Stevens‑Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are
Medical College, Bhavnagar,
Gujarat, India rare severe cutaneous drug reactions. No large scale epidemiological data are available for
this disorder in India. Aims: To carry out a systematic review of the published evidence of the
Address for correspondence: drug‑induced SJS and TEN in Indian population. Methods: Publications from 1995 to 2011
Dr. Tejas K. Patel, describing SJS and TEN in Indian population were searched in PubMed, MEDLINE, EMBASE
Department of Pharmacology, and UK PUBMED Central electronic databases. Data were collected for the causative drugs
GMERS Medical College, and other clinical characteristics of SJS and TEN from the selected studies. Results: From 225
Gotri ‑ 390 021,
references, 10 references were included as per selection criteria. The major causative drugs
Gujarat, India.
E‑mail: were antimicrobials (37.27%), anti‑epileptics (35.73%) and non‑steroidal anti‑inflammatory
[email protected] drugs (15.93%). Carbamazepine (18.25%), phenytoin (13.37%), fluoroquinolones (8.48%)
and paracetamol (6.17%) were most commonly implicated drugs. Regional differences were
observed for fluoroquinolones, sulfa drugs and carbamazepine. Total 62.96% of patients
showed systemic complications. Most common complications were ocular (40.29%) and
septicemia (17.65%). Higher mortality was observed for TEN as compared to SJS (odd
ratio‑7.19; 95% confidence interval (CI) 1.62‑31.92; p = 0.0023). Observed mortality is higher
than expected as per SCORTEN score 3. Duration of hospital stay was significantly higher
in TEN (20.6 days; 95% CI 14.4‑26.8) as compared to SJS (9.7 days; 95% CI 5.8‑13.6;
p = 0.020). Cost of management was significantly higher in TEN (` 7910; 95% CI 5672‑10147;
p < 0.0001) as compared to SJS (` 2460; 95% CI 1762‑3158). No statistical data were
described for steroid use in the studies included. Conclusion: Carbamazepine, phenytoin,
fluoroquinolones and paracetamol were the major causative drugs. TEN is showing higher
mortality, morbidity and economic burden than SJS.

Key words: Causative drugs, corticosteroids, India, SCORTEN score, Stevens‑Johnson

syndrome, toxic epidermal necrolysis

INTRODUCTION reactions endangering patient’s life. Incidence of SJS

and TEN is 2.6‑7.1 persons per million populations
Stevens‑Johnson syndrome (SJS) and toxic epidermal per year in United States.[1,2] It is 1.1 and 0.93 per
necrolysis (TEN) are rare but severe cutaneous drug million per year for SJS and TEN respectively in
Germany.[3] Drugs are most commonly implicated
Access this article online
for causing 77‑95% of cases.[4,5] SJS/TEN have been
Quick Response Code: Website: observed with more than 100 drugs. Common
www.ijdvl.com
culprits are antimicrobials, anti‑epileptic drugs and
DOI: non‑steroidal anti‑inflammatory agents (NSAIDs).
10.4103/0378-6323.110749

PMID: SJS and TEN involve <10% and >30% of the body surface
*****
area respectively. The third condition named as SJS‑TEN

How to cite this article: Patel TK, Barvaliya MJ, Sharma D, Tripathi C. A systematic review of the drug-induced Stevens-Johnson
syndrome and toxic epidermal necrolysis in Indian population. Indian J Dermatol Venereol Leprol 2013;79:389-98.
Received: October, 2012. Accepted: December, 2012. Source of Support: Nil. Conflict of Interest: None declared.

Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3 389
Patel, et al. Systematic review of Stevens‑Johnson syndrome and toxic epidermal necrolysis

overlap falls in‑between SJS and TEN.[6] Patient may outdoor patients)
initially present with SJS, which subsequently evolves Exclusion criteria
into TEN or SJS‑TEN overlap. Diagnosis mainly relies • Studies not conducted in Indian population
on clinical signs and histopathology of skin lesions.[7] • Studies not specifically describing the causative
The exact mechanism of SJS/TEN still remains largely drugs
unknown. Immunological mechanisms, reactive drug • Case series or case reports with less than
metabolites or interactions between these two are 10 cases of SJS and TEN
proposed. Interactions between CD95 L and Fas (CD 95)
are directly involved in the epidermal necrolysis.[8,9] Review methods
Granulysin is also considered as a key mediator for The ‘STROBE statement’‑a reporting guideline with
disseminated keratinocyte death in SJS/TEN.[8] checklists for the observational studies that are
considered essential for good reporting was used to
Being a rare disease, there is a lack of large sample assess the quality of the included studies.[10,11] For each
Indian studies. The main purpose of this study is to study, information was collected for the causative
carry out a systematic review of published literature to drugs for SJS/TEN. Selected studies were divided into
generate a large‑scale database in the form of causative four regions (North, South, East and West) according to
drugs, differences in the regional distribution of drugs, Central Drug Standard Control Organization (CDSCO)
clinical outcome and economic burden in Indian zonal distribution to compare the primary outcome
population. variable – causative drugs.[12] Other data collected were
demographic, type of clinical settings, ADR causality
METHODS assessments, incubation period, prodromal and
clinical features, co‑morbid conditions, complications,
The search was focused on publications describing duration of hospital stay, cost of management,
drug‑induced SJS/TEN in Indian population. SCORTEN score, mortality and use of corticosteroids.
The search strategy included the following key
terms: ‘TEN’ OR ‘SJS’ OR ‘cutaneous adverse Outcome analysis
drug reactions (ADR)’ AND (‘India’ OR ‘Indian Data for primary outcome variable were extracted from
population’). The search included the electronic the studies and summarized using absolute numbers of
databases‑PubMed, MEDLINE, EMBASE and UK cases and percentage. Subgroup analysis was performed
PUBMED Central. It also included the review of for four regions of India and Chi‑square test was used
bibliographies of relevant articles. Article published to compare the proportion of causative drugs. Data
from 1995 to 2011 were included. Articles only for secondary outcome variables were extracted and
in English language were considered. Studies were summarized using ranges, means and proportions as
selected by two reviewers independently by the search provided by the authors. Combined mean and standard
from July 2011 to February 2012. Title, abstract and deviation were calculated for the incubation period.
if required full articles from the retrieved references Prodromal and clinical features were summarized
were assessed for possible inclusion into the study. qualitatively. Data for the complications, co‑morbid
Review articles, commentaries and editorials were conditions, abnormal laboratory parameters, mortality
excluded. Protocol of this study was registered and SCORTEN score were pooled and presented as
in the PROSPERO register for the systematic proportions. Percentage of mortality between SJS
review (Center for reviews and dissemination (CRD) and TEN was compared by Chi‑square test. Duration
42011001872). of hospital stay, cost of management and use of the
corticosteroids were summarized as presented by
Inclusion criteria the authors. Any disagreements were discussed and
• Studies in Indian population resolved by a consensus and by a third reviewer. SPSS
• Case‑control, cohort studies and case software version 17.0 was used for statistical analysis.
series (including at least 10 cases) of SJS and p < 0.05 was considered significant.
TEN
• Studies of ADR or cutaneous ADR (prospective RESULTS
or retrospective) including at least 10 cases of
SJS and TEN Literature search
• All age groups and clinical settings (indoor or The literature search yielded 225 references, of

390 Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3
Patel, et al. Systematic review of Stevens‑Johnson syndrome and toxic epidermal necrolysis

which 204 were excluded as per criteria. Twenty one From that seven studies, the number of patients with
references were fully evaluated, and 10 were included SJS, TEN and SJS‑TEN overlap were 144 (50.17%),
as per criteria for the final analysis.[13‑22] 120 (41.81%) and 23 (8.01%) respectively. Maximum
numbers of cases were in the age group of 21‑40 years.
Characteristic and quality of the studies included Male‑female ratio was 1:1.13.[17‑19,21,22] The youngest
Among ten included studies, five were prospective and patient was a three‑year‑old child and the eldest was a
five were retrospective case series. We did not find any 78‑year‑old male [Table 2].
cohort or case‑control study. Two studies were from
North, four from the South, three from the West and Causative drugs
one from the East India. Four studies followed WHO Drugs were implicated in 342 (97.14%) out of 352
causality analysis[14‑16,20] and one followed Naranjo’s total cases. Total 389 encounters with prescribed
algorithm.[22] Five studies did not mention the drugs (average 1.14 drugs per case) were suspected.
causality assessment [Table 1].[13,17‑19,21] Bastuji‑Garin S On analysis, the total number of drugs was 58 as
et al.[6] classification was used by two studies for the same drug have been prescribed more than once in
diagnosis of SJS/TEN.[19,21] Clinical and morphological different patients. Out of the 10 studies, six studies
grounds were mentioned by five studies.[13‑15,17,22] have not differentiated the SJS, TEN and SJS‑TEN
Studies adhered poorly to the ‘STROBE statement’ overlap separately for describing the causative
recommendations.[10,11] drugs.[13,16‑18,20,21] So, no differentiation was made
between SJS, TEN and SJS‑TEN overlap in this study.
Characteristics of the patients Antimicrobials (37.27%), anti‑epileptic drugs (35.73%)
In above 10 studies, 352 cases of SJS/TEN were and NSAIDs (15.93%) were the major causative
reported. Seven studies differentiated the cases into drugs [Table 3]. Total 30 different antimicrobials
SJS, TEN and SJS‑TEN overlap category.[13‑15,18,19,21,22] were suspected. Carbamazepine (18.25%),

Table 1: Characteristics of the included studies

Studies Design Region/place Type of patients ADR‑causality analysis
Sharma et al.[13] PCS Chandigarh, India (N) OPD and indoor NR
Noel et al.[14] PCS Banglore, Karnataka (S) Indoor WHO causality definitions
Sushma et al.[15] RCS Banglore, Karnataka (S) Indoor WHO causality definitions
Chatterji et al.[16] PCS Kolkata, West Bengal (E) Indoor WHO causality definitions
Devi et al.[17] RCS Thrissur, Kerala (S) Indoor NR
Vaishampaiyyan et al. [18]
PCS Pune, Maharashtra (W) Indoor NR
Sharma et al.[19] RCS New Delhi (N) Indoor NR
Shristava et al.[20] PCS Nagpur, Maharashtra (W) OPD and Indoor WHO causality definitions
Sanmakaran et al.[21] RCS Pondicherry (S) Indoor NR
Barvaliya et al.[22] RCS Gujarat (W) Indoor Naranjo’s algorithm
ADR: Adverse drug reactions, OPD: Outdoor patient department, WHO: World health organization, PCS: Prospective case‑series, RCS: Retrospective
case‑series, (N), (S), (E), (W): North, South, East and West zone of India respectively, NR: Not reported

Table 2: Demographics of the patients

Study No. of patients SJS/TEN/overlap Age in years range (max age groups) M/F
Sharma et al. [13]
57 24/33/0 NR (21 to 40) NR
Noel et al.[14] 16 7/9/0 NR (21 to 40) NR
Sushma et al.[15] 96 75/21/0 NR (21 to 40) NR
Chatterji et al.[16] 12 NR NR NR
Devi et al.[17] 41 NR 12 to 72 (20 to 30) 1:1.05 (20/21)
Vaishampaiyyan et al.[18] 10 0/6/4 3 to 70 (10 to 40) 1:1.5 (4/6)
Sharma et al.[19] 30 6/15/9 4 to 65 (NR) 1:1.30 (13/17)
Shristava et al.[20] 12 NR NR (21 to 40) NR
Sanmakaran et al.[21] 46 21/21/4 3 to 78 (11 to 30 years) 1:1.23 (21/26)
Barvaliya et al.[22] 32 11/15/6 7 to 60 (NR) 1.13:1 (17/15)
Total 352 144/120/23 3 to 78 years 1:1.13 (75/85)
SJS: Stevens‑johnson syndrome, TEN: Toxic epidermal necrolysis, NR: Not reported

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Patel, et al. Systematic review of Stevens‑Johnson syndrome and toxic epidermal necrolysis

Table 3: Drugs causing stevens‑johnson syndrome/toxic epidermal necrolysis

Causative drugs Total no (%) Causative drugs Total no. (%)
Antimicrobial drugs 145 (37.27) Anti‑epileptic drugs 139 (35.73)
Fluoroquinolones 33 (8.48) Carbamazepine 71 (18.25)
Gatifloxacin 5 Phenytoin 52 (13.37)
Ciprofloxacin 4 Phenobarbitone 11 (2.83)
Ofloxacin 2 Sodium valproate 2 (0.52)
Pefloxacin 1 Lamotrigine 1 (0.26)
Levofloxacin 1 Others NS anti‑epileptics 2 (0.52)
NS 20 NSAIDS 62 (15.93)
Anti‑tubercular 22 (5.65) Paracetamol 24 (6.17)
Isoniazid 1 Nimesulilde 11 (2.83)
Pyrizinamide 1 Diclofenac 8 (2.06)
Rifampicin 1 Ibuprofen 4 (1.02)
NS 19 Vicks action 500* 2 (0.52)
Penicillins 21 (5.39) Aspirin 1 (0.26)
Amoxycillin 6 Mefenamic acid 1 (0.26)
Ampicillin+Cloxacillin 3 Piroxicam 1 (0.26)
Ampicillin 2 Paracetamol+Ciprofloxacin 1 (0.26)
Penicliin 1 Anacin** 3 (0.77)
NS 9 Analgin*** 3 (0.77)
Anti‑retro viral 13 (3.34) Others NS NSAIDs 3 (0.77)
Nevirapine 11 Other drugs 16 (4.11)
Zidovudine 1 Antisecretory rugs 4 (1.02)
Stavudine 1 Ranitidine 2
Sulpha drugs 24 (6.16) Famotidine 1
Cotrimoxazole 12 (3.08) Pantoprazole 1
Sulphonamides 12 (3.08) Antiemetics 3 (0.77)
Cephalosporins 12 (3.08) Ondansetron 1
Cefixime 1 Domperidon 2
Cefadroxyl 1 Diuretics 2 (0.52)
Ceftriaxone 1 Furosemide 1
Cephalexin 1 NS 1
Cefotaxime 1 Multivitamins 2 (0.52)
NS 7 Allopurinol 2 (0.52)
Antimalarial 5 (1.28) Chlorpromazine 1 (0.26)
Pyrimethamine+Sulfadoxine 2 Amlodipine 1 (0.26)
Quinine 2 Leflunomide 1 (0.26)
Chloroquine 1 Unknown drugs 28 (7.19)
Tetracyclines 4 (1.02) Ayurvedic medication 4 (1.02)
Doxycycline 3 P. amarus (Kizhaneli) 1
NS 1 Ayurvedic medication NS 3
Aminoglycosides 3 (0.77) Siddha 1 (0.26)
contd...

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Patel, et al. Systematic review of Stevens‑Johnson syndrome and toxic epidermal necrolysis

Table 3: Contd...
Causative drugs Total no (%) Causative drugs Total no. (%)
Amikacin 1 Total drugs 389 (100)
Gentamycin 1
NS 1
Macrolides 3 (0.77)
Erythromycin 1
NS 2
Chloramphenicol 1 (0.26)
Others NS antimicrobials 4 (1.02)
NSAIDs: Non‑steroidal anti‑inflammatory agents, NS: Not specified. Few studies had presented the causative drugs as a pharmacological group (e.g.,
fluoroquinolones, antituberculars, tetracyclines, etc.) and system (e.g., antimicrobials) rather than individual drugs. NS is used to represent them. *Paracetamol+ph
enylpropanolamine+caffeine, **aspirin+caffeine, ***acetylsalicylic acid+paracetamol+codeine phosphate+caffeine

phenytoin (13.37%), fluoroquinolones (8.48%) and in 159 patients.[17‑19,21,22] Human immunodeficiency

paracetamol (6.17%) were found to be the most virus (HIV) infection (18 cases‑11.32%),
commonly implicated. West Indian,[18,20,22] North diabetes (9 cases‑5.66%), carcinoma (6 cases‑3.77%),
Indian[13,19] and South Indian[14,15,17,21] studies were hypertension (5 cases‑3.14%) and tuberculosis
compared to find out the regional differences between (5 cases‑3.14%) were commonly observed.[17‑19,21,22]
causative drugs. Due to small sample size, East Indian Reported cases of malignancy were non‑Hodgkin’s
study[16] was excluded from comparison. There was no lymphoma (3.57%), fibrillary astrocytoma (1.79%),
regional difference between frequency of distributions carcinoma breast (1.79%), and carcinoma
of antimicrobials, anti‑epileptics and NSAIDs as a cervix (1.79%).
group [Table 4]. In individual causative drugs, regional
differences were observed for fluoroquinolones, Complications and mortality
sulfa drugs and carbamazepine. South Indian Complications were described in three
studies had reported higher percentage of cases with studies.[19,21,22] Total 62.96% (68 out of 108) of patients
fluoroquinolones (p = 0.001), whereas West and North developed systemic complications. Most common
Indian studies had reported higher percentage of complications [Table 5] were ocular (40.29%)
cases with sulfa drugs (p = 0.0134). Carbamazepine comprising symblepharon, hypopyon, corneal
was the most common causative drug from the North scarring, viral or bacterial conjunctivitis,
and South Indian studies (p = 0.0407). No regional blepharitis and corneal xerosis. Others were
difference was noted for phenytoin and paracetamol. septicemia (17.65%), secondary infections (13.23%),
pneumonitis (8.82%) and acute renal failure (ARF)
Incubation period and clinical features (7.35%). Abnormal laboratory parameters [Table 6]
Duration between the drug intake and the first were observed in four studies[18,19,21,22] included altered
onset of a symptom was ranged between few h and hematological (41.54%), liver functions (39.43%),
45 days. Average incubation period pooled from three electrolytes (7.04%), hyperglycemia (6.33%) and
studies[18,19,22] was 16.47 ± 10.62 days. Prodromal renal functions (5.63%). Average number of abnormal
features fever, cough, sore throat, headache, myalgia, laboratory parameters per patient was 1.20. Overall
and burning sensation were described in two mortality was 12.94%; 3.92% in SJS; 5.26% in
studies.[19,21] As described by Sanmarkan et al.,[21] skin SJS‑TEN overlap and 28.20% in TEN cases.[13‑19,21,22]
lesions preceded mucosal lesions in 50% of patients. Higher mortality observed in TEN as compared to SJS
Oral, conjunctiva and genital mucosa were involved was significant (odd ratio‑7.19; 95% CI: 1.62‑31.92;
in 43.47% of patients.[21] However, oral mucosal p = 0.0023 by Chi‑square test). Antimicrobials (42.10%),
scarring was not observed by Devi et al.[17] Authors anti‑epileptics (26.31%) and NSAIDs (15.79%) were
had co‑related it with the early use of corticosteroids the causative drugs in the expired patients.[14,15,17,18,21]
in their patients.[17] Total 14 out of 18 patients (77.78%) died had one of
the associated co‑morbid conditions like the HIV
Co‑morbid conditions infection (5), diabetes (4), malignancy (2), chronic
Total 52 (32.70%) co‑morbid conditions were observed alcoholism (1), head injury with coma (1) and

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Patel, et al. Systematic review of Stevens‑Johnson syndrome and toxic epidermal necrolysis

Table 4: Regional distribution of causative drugs Table 5: Complications associated with stevens‑johnson
syndrome/toxic epidermal necrolysis
Causative drugs South West India North p value
India n (%) n (%) India n (%) Complications No. (%)
Antimicrobials 72 (40) 40 (49.38) 33 (28.69) 0.1393 Ocular 27 (40.29)
Fluoroquinolones 26 6 1 0.0010* Septicemia 12 (17.65)
Sulpha drugs 5 10 11 0.0134* Secondary infection 9 (13.23)
Antiepilepsy drugs 68 (37.36) 16 (19.75) 46 (40) 0.0704 Pneumonitis 6 (8.82)
Carbamazepine 42 7 17 0.0407* Acute renal failure 5 (7.35)
Phenytoin 20 8 20 0.2810 Urinary tract infection 2 (2.94)
NSAIDS 27 (14.83) 18 (22.22) 16 (13.91) 0.3685 Congestive cardiac failure 2 (2.94)
Paracetamol 8 10 6 0.0688 Pulmonary edema 2 (2.94)
Total drugs 182 (100) 81 (100) 115 (100) ‑ Metabolic encephalopathy 1 (1.47)
NSAIDs: Non‑steroidal anti‑inflammatory agents, *p<0.05 by Chi‑square test Hepatic encephalopathy 1 (1.47)
Intracranial bleed 1 (1.47)
Table 6: Abnormal laboratory parameters Total 68 (100)

Laboratory parameters No. (%)

Hematological 59 (41.54) Table 7: Comparison between expected and observed
Leucocytosis 25 mortality by SCORTEN score
Leucopenia 12 SCORTEN score Total number Observed Expected mortality
Lymphopenia 4 at admission of cases mortality % % (95% CI)[23]
Eosinopenia 3 0‑1 21 9.52 3.1 (0.1‑16.7)
Anemia 11 2 14 14.28 12.1 (5.4‑22.5)
Thrombocytopenia 4 3 05 80 35.3 (19.8‑53.3)
Hepatic 56 (39.43) 4 02 50 58.3 (36.6‑77.9)
Increased aminotransferases 26 5 or more 00 00 >90 (55.5‑99.8)
Increased alkaline phosphatases 18 CI: Confidence interval

Hyperbilirubinemia 5
Altered liver functions 7
Duration of hospital stay and management cost
Electrolytes 10 (7.04)
Data of duration of hospital stay and management cost
Hypokalemia 5
were described by Barvaliya et al.[22] Hospitalization
Reduced HCO3 4
was 9.7 days (95% CI: 5.8‑13.6) in SJS, 16.1 days (95%
Hyperkalemia 1
CI: 5.0‑27.4) in SJS‑TEN overlap and 20.6 days (95%
Renal‑Raised BUN 8 (5.63)
Hyperglycemia 9 (6.33)
CI: 14.4‑26.8) in TEN. It was significantly higher in
Total 142 (100) TEN as compared to SJS (p = 0.020, Tukey‑Kramer
HCO3: Bicarbonate, BUN: Blood urea nitrogen Multiple comparisons test). Management cost was
Rs 2460 (95% CI: 1762‑3158) in SJS, Rs. 4857 (95%
hypothyroidism (1).[15,17,18,21] The presence of a severe CI: 2118‑7587) in SJS‑TEN overlap and Rs 7910 (95%
systemic illness before the onset of SJS/TEN was a bad CI: 5672‑10147) in TEN that was significantly higher
prognostic factor.[17] The most common cause of death as compared to SJS (p < 0.0001, Tukey‑Kramer
was septicemia.[13,17‑19,21] ARF, acute respiratory distress Multiple comparisons test).[22] The cost was based on
syndrome (ARDS) and multiple organ dysfunctions drugs, investigations and consumables used. Direct
were other reported causes.[13,17,21] nonmedical and indirect costs were not mentioned.[22]

SCORTEN score Use of corticosteroids

SCORTEN was reported in three studies.[18,21,22] No detailed description of corticosteroid
Sanmarkan et al. mentioned its range from 0 to 5 in the use was found in the studies. Two studies
TEN patients. Data were pooled from other two studies have recommended early short‑term use of
to calculate the percentage of mortality according to dexamethasone.[19,21] Sharma et al.[19] described the
score at the time of admission.[18,22] Observed mortality use of parenteral dexamethasone (4‑8 mg/day) or
rate matches with the expected mortality rate,[23] equivalent steroids for a short course of 2‑12 days in
except higher mortality was observed for SCORTEN tapering doses in 29 patients with early active disease
score 3 [Table 7]. or with the reappearance of erythema in recovering

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Patel, et al. Systematic review of Stevens‑Johnson syndrome and toxic epidermal necrolysis

patients. Lag period for the starting of treatment in early patients.[25] Though the total reported cases with
active cases was not mentioned. Sanmakaran et al.[21] nevirapine are 11 (2.83%) in our study; this drug
reported onset of healing on 3rd day in patients on should be monitored because of its widespread use as
the dexamethasone pulse. Short term dexamethasone a first‑line anti‑retroviral drug in India. It should be
may reduce mortality without improvement in discontinued as soon as eruption occurs.[30] Patterns of
healing. Earlier onset of healing i.e., on 2nd day and the most common reported antimicrobials varies from
lowest period of hospitalization was also noted for country to country. In our study, anti‑tubercular drugs
methyl‑prednisolone therapy. However, dosage, route are found as the third most common cause which
and lag period for administration of dexamethasone and does not match with European studies probably due
methyl‑prednisolone were not described.[21] Devi et al.[17] to low disease burden there. In Togo, eight cases of
described the use of systemic dexamethasone (4‑12 mg/ SJS/TEN have been observed in HIV‑infected patients
day in divided doses parenterally) for a period of two taking combination of rifampicin and isoniazid.[31] Few
weeks in tapering doses under cover of antibiotics in cases of SJS/TEN due to tetracyclines, antimalarials,
36 patients within 2‑3 days of onset of symptoms. They aminoglycosides, macrolides and chloramphenicol are
observed complete recovery in patients without having reported in our study. Considering their widespread
underlying systemic disease and no mucosal scaring in use across India, risk seems minimal.
the eyes.[17]
In this study, carbamazepine (18.25%) and
DISCUSSION phenytoin (13.37%) are most commonly involved
anti‑epileptic drugs. They are widely used in India.[32,33]
In the present study, clinical characteristics Carbamazepine and phenytoin are also reported as
of SJS/TEN in Indian population are systematically most common anti‑epileptic drugs for SJS/TEN in
reviewed from the selected studies from 1995 to Taiwan.[34] Carbamazepine is the most the common
2011. The age of patients with SJS/TEN ranges from and the only anti‑epileptic reported from Japan and
3 years to 78 years. The majority of the patients are Singapore.[24,27] SCAR study has reported association
in the range of 21‑40 years that matches with the of SJS/TEN with phenobarbitone, carbamazepine,
reports from other countries.[24] Female preponderance phenytoin and sodium valproate.[29] Subsequent
observed here is similar to other studies abroad.[24,25] EuroSCAR study did not find significant risk with
No seasonal variation is documented in any of these sodium valproate.[25] The association of sodium
studies as reported by Wanat et al.[26] valproate seems to be confounded by concomitant
use of other anti‑epileptic drugs.[25,35] In our study,
The major causative drugs are antimicrobials, merely two cases are suspected due to sodium
anti‑epileptics and NSAIDs. Thirty three antimicrobials valproate. Considering its widespread use,[33] risk
from 11 groups are implicated. Most common are of SJS/TEN seems insignificant in India. EuroSCAR
fluoroquinolones (8.48%), sulpha drugs (6.68%), found a significant risk with lamotrigine.[25] The risk
anti‑tubercular drugs (5.65%), penicillins (5.39%), estimates of SJS/TEN vary between 1 and 10 per
anti‑retro virals (3.34%) and cephalosporins (3.08%). 10,000 in current users of carbamazepine, lamotrigine,
One study from Singapore[27] reports highest incidence phenytoin and phenobarbitone.[36] We have found only
with β‑lactam antibiotics that almost matches this study one case with lamotrigine. This is probably due to its
if penicilins and cephalosporins above are considered limited utilization in our country.[33] Among cases
together. Cephalosporins are the most common culprit exposed to anti‑epileptic drugs in EuroSCAR study,
reported from Japan.[24] Sulphonamides (50.6%) and 85‑100% of patients have initiated their treatment
nevirapine (23.6%) are most commonly implicated less than 8 weeks before the reaction.[25] Risk for
drugs from Togo.[28] Association of antimicrobials the development of SJS/TEN with anti‑epileptics is
with SJS/TEN is suspected to be a confounding factor largely confined to initial 8 weeks.[25,35] This should
if they are given during fever before the appearance be considered for analyzing the causal relationship
of skin manifestations. However, severe cutaneous between anti‑epileptic drugs and SJS/TEN.
adverse reactions (SCAR) study has found significant
increase risk of SJS with sulfa drugs, aminopenicillins, Among the NSAIDs, paracetamol and nimesulide are
quinolones and cephalosporins after ruling out recent most common reported in this study. SCAR study has
infections as a confounding factor.[29] In EuroSCAR found an overall risk of SJS with oxicam derivatives.
study, nevirapine is the leading culprit in HIV‑positive It reports increased risk with paracetamol from
Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3 395
Patel, et al. Systematic review of Stevens‑Johnson syndrome and toxic epidermal necrolysis

Germany, Italy, and Portugal except France. There HLA‑B*1502 and SJS/TEN.[42] One study from India
is no increased risk with diclofenac, salicylates and reports HLA‑B*1502 in six out of eight patients
pyrazolone derivatives.[29] EuroSCAR study found weak of carbamazepine‑induced SJS/TEN.[43] Phenytoin
association of paracetamol with SJS.[25] Paracetamol is possesses an aromatic ring like carbamazepine. In
confounded by its use to treat nonspecific symptoms one case‑control study from Taiwan, HLA‑B*1502
such as fever or pain, the early signs of the adverse was present in 8 out of 26 (30.8%) patients of
reaction or infection both.[25] However, pararacetamol phenytoin‑induced SJS and 3 out of 3 (100%) in
is found to be a potential risk factor in children when patients of oxacarbazepine‑induced SJS. These drugs
data from pediatric patients from the SCAR and should also be avoided in HLA‑B*1502 carriers.[44]
EuroSCAR studies are pooled.[37] Out of the 10 included
studies, eight had mentioned the paracetamol as a HIV is the most common co‑morbid condition in the
suspected causative agent.[14,15,17‑22] However, causality patients of SJS/TEN in India. Observed proportion of
analysis was done by four studies only. Three of HIV‑positive patients in the present study is lower
them used WHO causality definitions,[14,15,20] and one than South Africa (78.67%), Togo (54.6%) and higher
used Naranjo’s algorithm.[22] No details about use of than France (7.3%).[28,45,46] Incidence rate of SJS is
paracetamol along with antimicrobials or other agents 1,000 fold higher in HIV‑positive patients as compared
are mentioned in any of the studies under review. to general population in Germany.[47] In contrast to
Higher reporting of paracetamol may be because it our study, higher cases of malignancy (10.6%) than
is widely prescribed and available over‑the‑counter. HIV infection (6.6%) were reported in EuroSCAR.[25]
Many other less prescribed drugs have more ADR than The patients had complications involving eye, liver,
paracetamol. In contrast to SCAR and EuroSCAR,[25,29] kidneys, lungs, and blood. In addition to septicemia,
we found only one case of SJS with piroxicam. Drug other problems in the course were ARF, ARDS
utilization studies of NSAIDs from India show the and multiple organ dysfunctions. Surviving sepsis
less use of piroxicam as compared to paracetamol, campaign (SSC) guidelines can be followed to reduce
ibuprofen and diclofenac.[38,39] the mortality due to septicemia, particularly in TEN
patients. It is developed by the international group
No regional differences in frequency of reporting of of the experts.[48] Various studies have shown the
antimicrobials, anti‑epileptic drugs and NSAIDs as reduced mortality following implementation of the
a group are observed. Carbamazepine, phenytoin SSC guidelines.[49,50] There is a wide difference in
and paracetamol are the most common culprit the mortality between SJS (3.92%) and TEN (28.2%).
drugs from the South, North and West India Higher mortality, duration of stay and management
respectively. A relative risk of SJS/TEN usually cost are observed in TEN as compared to SJS that is
remains uniform geographically. The prevalence of in accordance with the studies abroad.[24,27,51] Data of
exposure to medication may vary between countries duration of stay and management cost were based on
and with the time period.[37] The observed regional one study only. More studies from India are required
differences for fluoroquinolones, sulfa drugs and to substantiate the data. Availability of facilities and
carbamazepine could be due to different utilization the level of care may have affected the mortality and
pattern of these drugs or because of under‑reporting. duration of stay.
We have not found any regional difference with
paracetamol as described by SCAR study.[29] Out of SCORTEN uses seven independent risk factors to
these drugs, genetic predisposition is only reported predict the risk of death: Age, malignancy, heart
with the carbamazepine. Strong association between rate, epidermal detachment, serum urea, glucose and
carbamazepine‑induced SJS with human leucocyte bicarbonate at admission.[23] In our study, in patients
antigen (HLA‑B*) 1502 is reported in the Han having SCORTEN score 3 at admission show higher
Chinese population.[40] HLA‑B*1502 allele is not a than expected mortality. The SCORTEN is associated
universal marker for this disease and it depends on with a greater risk of day to day varying mortality
ethnicity.[41] The association has not been found in during first 5 days of hospitalization. Its performance is
Caucasian patients. However, this allele is seen in best at day three.[52] Vaishampaiyyan et al.[18] observed
high frequency in many Asian populations. The US the progression of score from the day of admission to
FDA has made a label change in drug information day five. SCORTEN score should be observed up to
about carbamazepine for a strong correlation between day 5 for the accurate prediction of mortality.

396 Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3
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5. Sehgal VN, Srivastava G. Toxic epidermal necrolysis (TEN)
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to analyze the effect of steroids from this study due multiforme. Arch Dermatol 1993;129:92‑6.
to limited description of their use. Early use of short 7. Harr T, French LE. Toxic epidermal necrolysis and
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8. Saha K. Toxic epidermal necrolysis: Current concepts in
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11. Vandenbroucke JP, von Elm E, Altman DG, Gøtzsche PC,
Mulrow CD, Pocock SJ, et al. Strengthening the Reporting of
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with suspected drugs in study population. So, we nic.in/Guidance%20document%20on%20application%20
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with the use of medication. There is also the strong for%20manufacture%20of%20Medical%20Devices%20
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